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EMS Genetics > pharmacogenetics > Flashcards

pharmacogenetics Flashcards

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1
Q

what is ivacaftor, what are the indications and what is the result?

A

it is a CF potentiator. The condition must have been confirmed by a biochemical test and it will benefit 1/25 patients

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2
Q

what is genomics?

A

it is relating to the genome - total DNA or RNS

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3
Q

what is the difference between pharmacodynamics and kinetics?

A

pharmacokinetics is what the body does to the drug and is being focused on by the NHS for a optimum tailored treatment for individuals, pharmacodynamics is what the drug does the body

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4
Q

what is stratified medicine?

A

selecting therapies for groups of people with shared biological characteristics

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5
Q

what is the difference between germline and somatic?

A

germline is hereditary and somatic is acquired in non germline cells and not hereditary

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6
Q

what is pharmacogenetics?

A

it is the study of genetic differences in the drug metabolism pathway that can affect how an individual will respond to a drug - adverse reaction or positively

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7
Q

what can pharmacogenetic be used in?

A

stratified and individualised medicine

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8
Q

what can all medications affect?

A

proteins - most commonly SNPs

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9
Q

how can promoter polymorphisms affect genes?

A

they affect the promoter and therefore gene transcription

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10
Q

what happens if you change the shape of the ligand?

A

cannot bind, changes the metabolism of the drug and outcome of treatment

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11
Q

what can result in a altered outcome to a treatment?

A

change in protein from translocations, SNPs, promoter polymorphisms, gene amplification, deletions and insertions

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12
Q

what do missense changes do?

A

affect protein structure or activity

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13
Q

what is the most common type of genetic variation?

A

SNPs

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14
Q

how can SNPs affect outcome?

A

they can change the shape, binding activity or AA sequence

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15
Q

what does proline result in?

A

it has a strange shape so changes the shape of any protein it is in

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16
Q

what is a missense mutation?

A

when the original DNA code for an AA is changed by replacement of a single nucleotide which makes the incorrect AA, producing a malfunctioning protein

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17
Q

how can genetic variations affect drugs?

A

X linked - only males affected
recessive variants - 2 needed to be affected
dominant - only one needed to be affected
mitochondrial inheritance - from mother

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18
Q

which mode of inheritance shows the most severe side effects?

A

autosomal recessive

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19
Q

why are single genes unlikely to explain all variability in drug effects?

A

drug pathways have complex metabolism as many variant will affect the response to therapeutics

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20
Q

what needs to happen to the drug once it is ingested?

A

it needs to be absorbed and passed around the body to the target area - absorption, activation, altered target, catabolism, excretion

21
Q

what can affect the process of drug absorption?

A

transporter effects - how it is distributed
activation - body can activate inactive drug or can overactivate - large reaction
alter rate of catabolism and excretion

22
Q

what are the consequences of getting drug dose wrong?

A

it can be inactive - will pas through the body with no effect so financially detrimental and waste resources. Excess means toxicities and adverse reactions (only around 2-5% of the drug will actually work and other will be broken down), and there will be a poor response if not enough so waste of treatment or hospital space

23
Q

why is it so important to find a method of determining the appropriate therapeutic?

A

abacavir was the first HIV drug given. It gave 1 in 17 people ADRs due to genetic variation and only 20% of people will respond to a certain cancer drug therefore use trial and error - wasteful of time and money and resources and giving toxic drugs to those who do not need.

24
Q

what did a UK study in 2004 find about ARDs?

A

6.4% of UK hospital admissions are from ARDs. 2.3% of these will die in hospital and it accounts for 4% of bed occupancy and has a median stay of 8 days.

25
Q

where do variations lie in cancer treatment?

A

in the tumour and in the patient

26
Q

how can genetics help drug prescribing?

A

find an algorithm to determine which drugs will work best for which types of patients so that can then find other options

27
Q

what is the plan for drugs in the NHS by 2025?

A

intergrated genomics - WGS for those who have ADR, find somatic mutations for certain types of cancer, change doses and types of drugs if needed, reintroduce older ones that have caused some ADRs in some patients but are effective, identify genetic variation leading to altered outcome, stratified or personalised medicine, reduce financial costs and guided drug development

28
Q

what is TPMT?

A

thiopurine methyltransferase

29
Q

what is azathioprine used for an inactivated by?

A

it is an immunosupressant that is used in organ transplantation but over use can result in bone thinning. This is inactivated by TMPMT

30
Q

what are 6-mercaptopurine and 6-thioguanine?

A

they are chemotherapies

31
Q

what results with a polymorphism in TPMT?

A

it reduces the protein activity and therefore if there are variants on both TPMT genes then severe toxicity results from chemotherapy

32
Q

what does TPMT convert chemo into?

A

6 meracptopurine and cytotoxic 9 thioguanine nucleotides are transformed into 6 methyl MP which is inactive

33
Q

what is the most common CF mutation?

A

the delta f508 mutation but as of yet there is no treatment and dual therapy is only effective in 46% of these patients

34
Q

when was ivacaftor first used?

A

2012

35
Q

what is ivacaftor used in and why is it so effective?

A

CF G551D mutations - this is because the protein shape is not altered so the ligand can bind - it significantly improves symptoms such as reduction in sweat chloride concentration and lung function improvement and it enhances the CFTR channel so the probability of it being open is greater whether they are homozygous or heterozygous

36
Q

what is CF caused by?

A

biallelic mutation of the CFTR gene

37
Q

what is succinylcholine?

A

it is a general anaesthetic that works by paralysing the respiratory muscles and usually lasts for a few minutes

38
Q

how can the anaesthetic effect of succinylcholine be increased?

A

variants in the enzyme that break it down

39
Q

what happens when there is a variant in the enzyme that stops the break down of succinylcholine?

A

rare BCHE (butyrylcholinesterase) gene variant - homozygotes have reduced activity meaning that effects last for up to an hour or more and if do not continue artificial ventilation then will die

40
Q

what is aminoglycoside induced hearing loss?

A

when aminoglycosides have a tendency to bind to patients rRNA and produce free radicals. This results in ototoxicity from a young age - maternal inheritance accounts for 30% of this

41
Q

what is the genetic basis of aminoglycoside induced hearing loss?

A

mitochondrial (maternal) MT-RNR1 gene encodes mitochondria 12s rRNA normally. A G>A mutation at nucleotide position 1555 will cause a non syndromic hearing loss at later ages or change the structure of rRNA to resemble E-coli 16S rRNA so aminoglycosides are more likely to bind resulting in irreversible hearing loss

42
Q

what is warfarin?

A

it is a widely used oral anticoagulant to reduce thrombosis or embolism that decreases the availability of vitamin K. If the dose is too high they are at risk or haemorrhage and too low at risk of clot.

43
Q

why does warfarin dosage vary so much in individuals?

A

up to 50% of the variation (up to 20x variation in individuals) is accounted for by two genes : the CYP2C9 gene (part of tye CYP450 family) and vitamin K oxidoreductase complex 1 gene (VKORC1)

44
Q

what is the role of warfarin in VKORC1?

A

it block VKORC1 meaning that vitamin K epoxide cannot be converted to vit K so y-glutamyl carboxylase cannot activate factors II, VII, IX, X for clotting

45
Q

what is tratuzumab?

A

it is herceptin - it is a monoclonal antibody against the HER2 receptor used in breast cancer treatment

46
Q

why is herceptin so beneficial?

A

over 20% of breast cancer have over expression of HER2 (human epidermal growth factor receptor 2) due to gene amplification and protein over expression

47
Q

what type of cancer is notoriously resistant to chemotherapy?

A

melanoma (only 5% is effective)

48
Q

a new medication has been introduced for melanoma, what is it and what is it’s role?

A

vemurafenib - shows a 48% response rate in melanoma - 50% of melanomas have a somatic mutation in the BRAF gene - these are BRAF inhibitor drugs

EMS Genetics (19 decks)

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